The introduction of combination antiretroviral therapy (cART) in the mid-1990s for the treatment of Human Immunodeficiency Virus (HIV)-infection has substantially reduced AIDS related morbidity and mortality. Non- AIDS related conditions including cardiovascular disease (CVD) in general, and coronary heart disease (CHD) in particular, are an increasing concern to HIV-infected patients, their providers and the HIV care management system. In addition to traditional CHD risk factors and the effect of HIV infection itself, recent evidence also suggests that specific antiretrovirals may increase a patient's CHD risk. Cumulative antiretroviral use may increase risk, in part, due to effects of some antiretrovirals on dyslipidemia and insulin resistance. Additional work indicates that recent exposure to specific antiretrovirals increases CHD risk independent of these metabolic effects. However, the existing clinical research has not been conclusive, and many of the larger studies evaluating CHD risk have not been conducted in the US, where different patient demographic and clinical characteristics may result in different CHD risks. Therefore, we propose to conduct analyses of the comparative safety and effectiveness of recent and long-term antiretroviral therapy on CHD morbidity and mortality, relying on a large HIV clinical cohort in the Southeastern United States (the UNC CFAR HIV Clinical Cohort) as well as the Medicaid and Medicare claims databases. Further we plan to employ novel and innovative internal and external calibration techniques to impute values of missing covariates in the administrative claims data based on available data in the clinical cohort. Our Specific Aims are to: (1) Estimate the association of recent (within 6 months of coronary heart disease event) and cumulative use of specific antiretroviral medications on incident coronary heart disease among HIV-infected patients in the UNC CFAR HIV Clinical Cohort study and the Medicaid and Medicare databases. (2) Validate Medicaid and Medicare based exposure and outcome measurements, as well as, inferential estimates for the association between antiretroviral use and coronary heart disease, using measures and estimates obtained from the UNC CFAR HIV Clinical Cohort study. (3) Evaluate calibration methodologies for adjusting estimates of the association between antiretroviral use and coronary heart disease in the Medicaid and Medicare data using data available through the UNC CFAR HIV Clinical Cohort study. This study will have direct and important relevance to the care and management of HIV-infected patients. Our proposal will also contribute to existing comparative effectiveness research methods, by employing novel and innovative internal and external calibration techniques to account for unmeasured confounding in administrative claims data relying on data available through other sources. PUBLIC HEALTH RELEVANCE: This study will directly influence the clinical care of HIV-infected patients and contribute to existing comparative effectiveness research methods, by employing novel and innovative calibration techniques to account for unmeasured confounding in administrative claims data relying on data available through other sources.